The PDE4 inhibitors roflumilast and rolipram augment PGE2 inhibition of TGF-β1 stimulated fibroblasts
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چکیده
Fibrotic diseases are characterized by the accumulation of extracellular matrix together with distortion and disruption of tissue architecture. Phosphodiesterase 4 (PDE4) inhibitors, by preventing the breakdown of cyclic AMP, can inhibit fibroblast functions and may be able to mitigate tissue remodeling. TGF-β1, a mediator of fibrosis, can potentially modulate cAMP by altering PGE2 metabolism. The current study assessed whether PDE4 inhibitors functionally antagonize the profibrotic activity of fibroblasts stimulated by TGF-β1. The PDE4 inhibitors roflumilast and rolipram both inhibited fibroblast-mediated contraction of three-dimensional collagen gels and fibroblast chemotaxis toward fibronectin in the widely studied human fetal lung fibroblast strain HFL-1 and several strains of fibroblasts from adult human lung. Roflumilast was approximately 10-fold more potent than rolipram. There was a trend for PDE4 inhibitors to inhibit more in the presence of TGF-β1 (0.05 < p <0.08). The effect of the PDE4 inhibitors was mediated through cyclic AMP stimulated protein kinase A (PKA), although a PKA-independent effect on gel contraction was also
منابع مشابه
PDE4 inhibitors roflumilast and rolipram augment PGE2 inhibition of TGF-{beta}1-stimulated fibroblasts.
Fibrotic diseases are characterized by the accumulation of extracellular matrix together with distortion and disruption of tissue architecture. Phosphodiesterase (PDE)4 inhibitors, by preventing the breakdown of cAMP, can inhibit fibroblast functions and may be able to mitigate tissue remodeling. Transforming growth factor (TGF)-beta1, a mediator of fibrosis, can potentially modulate cAMP by al...
متن کاملPDE4 inhibitors roflumilast and rolipram augment PGE2 inhibition of TGF- 1-stimulated fibroblasts
Shinsaku Togo, Xiangde Liu, Xingqi Wang, Hisatoshi Sugiura, Koichiro Kamio, Shin Kawasaki, Tetsu Kobayashi, Ronald F. Ertl, Youngsoo Ahn, Olaf Holz, Helgo Magnussen, Karin Fredriksson, C. Magnus Skold, and Stephen I. Rennard Pulmonary and Critical Care Medicine, University of Nebraska Medical Center, Omaha, Nebraska; Third Department of Internal Medicine, Wakayama Medical University, Wakayama; ...
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